High doses of commonly used non-steroidal anti-inflammatory drugs (NSAIDs) could significantly increase the risk of major vascular and coronary events, a study in the Lancet has found.

This meta-analysis covered 280 trials of NSAIDs versus placebo, involving 124,513 patients, and 474 trials of one NSAID versus another, involving 229,296 patients. Daily treatment with cyclo-oxygenase 2 (COX 2) inhibitors, such as celecoxib and etoricoxib, or high-dose daily regimens of ibuprofen (2,400 mg), diclofenac (150 mg), and naproxen (1,000 mg) were analysed for cardiovascular and gastrointestinal side effects.

The primary vascular outcome was major vascular events (non-fatal MI, non-fatal stroke, or vascular death). Subsidiary vascular outcomes included major coronary events (non-fatal MI or coronary death); stroke; and hospitalisation for heart failure.

The primary gastrointestinal outcome was upper gastrointestinal complications (perforation, obstruction, or bleed).

Major vascular events were increased by about a third by a coxib, rate ratio (RR) 1·37 and diclofenac RR 1·41, see table 1 below. This was mainly driven by an increase in major coronary events: coxibs RR 1·76; diclofenac RR 1·70.

Ibuprofen also significantly increased major coronary events RR 2·22. However, neither ibuprofen nor naproxen significantly increased major vascular events.

Vascular death was increased significantly by coxibs RR 1·58 and diclofenac RR 1·65, non-significantly by ibuprofen, but not by naproxen.

Risk of hospital admission for heart failure was doubled by all NSAIDs, see table 1.

The proportional effects on major vascular events were independent of baseline characteristics, including vascular risk.

All NSAID regimens increased upper gastrointestinal complications.

The authors conclude that the vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable with those of coxibs, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs.

They calculate that of 1,000 patients allocated to a coxib or diclofenac for a year, there will be three more major vascular events, one of which will be fatal (baseline event rate 8/1,000/year).

This is a large analysis of trials across the globe and should further inform us to consider carefully the risk/benefit ratio of these drugs particularly for long-term use.

Dr Peter Savill